A bevy of forthcoming immunotherapies for multiple myeloma over the next few years raises hopes, as well as questions about combinations, sequencing, and potential for a new standard of care for frontline therapy.
The approval of the antibody drug conjugate belantamab mafodotin is the latest advance in immunotherapy for multiple myeloma (MM), but approvals of chimeric antigen receptor (CAR) T-cell therapies and bispecific antibodies could be next.
This leaves the standard of care in MM in flux as clinicians grapple not only with emerging efficacy and safety data across treatment modalities, but also with questions around new therapy combinations and sequencing. Experts agree that this evolution will ultimately benefit patients, even if it falls short of a cure.
"Until we cure myeloma in a high proportion of patients, what most patients [can expect] is many years of sequencing therapies," Luciano J. Costa, MD, PhD, associate director for clinical research at O'Neal Comprehensive Cancer Center at the University of Alabama at Birmingham, told ASH Clinical News. "Of course, the more options we add, and the better and safer those options are, the better off patients are going to be."
Antibody Drug Conjugates Score First
Antibody drug conjugates (ADCs) were the first immunotherapy class out of the gate for MM. On August 5, 2020, the U.S. Food and Drug Administration (FDA) granted accelerated approval to belantamab mafodotin-blmf for adults with relapsed/refractory MM who had already received at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.1 Belantamab mafodotin-blmf targets BCMA and has a unique conjugated cytotoxic agent.
The approval was made on the strength of results from the phase II DREAMM-2 trial, in which the agent demonstrated a 31% overall response rate (ORR) in participants who were dosed intravenously once every three weeks with 2.5 mg/kg. The median duration of response was not reached at the six-month cutoff, but 73% of patients who achieved a response to treatment had a duration of response of at least six months.2,3 After a longer follow up of 13 months, the median duration of response was 11 months and the overall survival was 13.7 months, according to Suzanne Trudel, MD, an associate professor and clinician scientist at the Princess Margaret Cancer Centre at the University of Toronto in Ontario, Canada, who was one of the investigators on the DREAMM-2 trial.
While belantamab was the first, there are other ADCs under investigation, including MEDI2228, which debuted its phase I, first-in-human trial findings at the 2020 American Society of Hematology (ASH) Annual Meeting. This ADC is comprised of a fully human antibody to B-cell maturation antigen (BCMA), site- specifically conjugated to a DNA cross-linking pyrrolobenzodiazepine dimer. After cell surface binding to BCMA, the active PBD is released, which cross-links DNA and leads to apoptotic cell death. MEDI2228 showed clinical efficacy at all dose levels, with an ORR of 61% in a heavily pretreated, relapsed/refractory patient population.4
As a class, the ADCs work much differently from other immunotherapies, such CAR T-cells and bispecific antibodies, Dr. Trudel explained. "The ADCs have a warhead associated with them and act like a directed missile to bring a cytotoxic drug to the cancer cell," she said. "We are seeing good activity with this particular class of drugs."
These agents also have a different toxicity profile from other immunotherapies. Dr. Trudel noted that investigators have not observed potentially life-threatening toxicities such as cytokine release syndrome (CRS) or neurologic toxicities, but the ADCs have so far shown frequent ocular toxicity. While not as clinically serious, the side effects can be "very distressing" for some patients, she said.
Belantamab mafodotin-blmf, which has the best-characterized safety profile among investigational ADCs, produces changes in the cornea in about two-thirds of patients. About 20% of patients experience blurred vision as a result. "That was the [FDA's] major concern with this particular drug," Dr. Trudel said.
As part of the FDA's accelerated approval, the agency required a boxed warning in the prescribing information indicating that the drug causes changes in the corneal epithelium that can cause symptoms such as vision loss, corneal ulcer, blurred vision, and dry eyes. The agency also required a Risk Evaluation and Mitigation Strategy (REMS) that includes ophthalmic exams at baseline and prior to administration of each dose of belantamab.
CAR T-Cell Therapies up Next?
The immunotherapy that experts say is the farthest along in development – and could be the next FDA-approved treatment in MM – is idecabtagene vicleucel (ide-cel). Researchers presented an update on this BCMA-directed CAR T-cell treatment at the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting.
At a median follow up of 11.3 months, the ORR was 73% and the median progression-free survival (PFS) was 8.6 months, both of which increased with higher doses of ide-cel. The findings were reported as part of the phase II KarMMa study, which included adults with heavily pretreated, relapsed/refractory disease.5
"It's strongly expected that this will be the first BCMA-directed CAR T-cell treatment to be considered by the FDA, and will likely be available sooner rather than later for patients with relapsed/refractory MM," said Sham Mailankody, MBBS, a medical oncologist and hematologist at Memorial Sloan Kettering Cancer Center in New York.
Another BCMA-directed CAR T-cell therapy receiving attention is ciltacabtagene autoleucel (cilta-cel), which is being investigated in the phase Ib/II CARTITUDE-1 trial. Dr. Mailankody called the results shared at the 2020 ASH Annual Meeting "very impressive," and added that this CAR T-cell product is likely headed toward approval by the end of 2021.
In the initial phase II data, cilta-cel demonstrated an ORR of around 95% and a median time to response of one month. The median duration of response was not reached.6
Dr. Mailankody has served as an investigator on a trial of another BCMA-directed CAR T-cell therapy, orvacabtagene autoleucel (orva-cel). In the most recent data from a phase I trial, presented at the 2020 ASCO annual meeting, the therapy showed an ORR of about 90%.7
All these CAR T-cell treatments target BCMA and are currently being tested in patients with advanced, refractory MM, but it is too early to make any head-to-head comparisons. "It's difficult to know if one is better or safer than others," Dr. Mailankody said. "The analogy I tell my patients is that it's like eating chocolate cake from five different bakers. They all use slightly different ingredients; they taste slightly different; but it's hard to pinpoint and say exactly what is going to be different."
"The BCMA space is becoming very busy. … It's extremely reassuring and refreshing to see validation of new immunotherapy targets."
—Luciano J. Costa, MD, PhD
These treatments have an important factor in common: high response rates. Data have proven that BCMA-directed CAR T cells are active in MM, with promising PFS, Dr. Mailankody said. "Unfortunately, we are seeing relapses in many of these studies, so it doesn't necessarily look like this is a one-time treatment that potentially cures disease," he said. "That may change in the future, but the available information suggests that, at some interval, patients' disease comes back and they will need additional treatments."
Side effects with the BCMA-directed CAR T cells are similar to what has been observed with CD19-directed CAR T cells used in treating leukemia and lymphoma, including CRS, neurotoxicity, and some degree of cytopenia that can persist for several weeks. But overall, the incidence of these toxicities appears lower than what was seen with the anti-CD19 products. In MM, the rates of grade ≥3 CRS are around 5% to 10%, while grade ≥3 neurologic events are about 3% to 4% for most products, Dr. Mailankody said.
Bispecific Antibodies and Off-The-Shelf Efficacy
The other major category of new immunotherapies is bispecific antibodies, which target both the myeloma cells and the T cells, forcing the recruitment of T cells into the tumor environment, explained Dr. Costa. He has been studying CC-93269, a BCMA-directed bispecific antibody that has been engineered to bind with two domains to BCMA and with one domain to CD3.
During the 2019 ASH Annual Meeting, Dr. Costa presented preliminary data on the first 30 patients treated with CC-93269 who were enrolled in a first-in-human phase I study. At a maximum dose of 10 mg, the researchers saw an ORR of 89% among participants with relapsed/refractory disease. Investigators also saw some durable responses, he said.8
"We had patients at the time approaching 12 months without progression," Dr. Costa said. "Almost all of those patients had triple-class refractory disease, representing a subset of patients that we know have a very dismal prognosis."
The trial also explored a step-up dosing strategy which allowed the researchers to help better manage potential side effects like CRS. "That strategy helps to trigger most of the CRS when the dose is lower, and almost invariably, the patients do not develop CRS with the second or third dose," he said. "That has proven to be a very effective mitigation strategy."
The study of CC-93269 is continuing and Dr. Costa expects to have extended follow-up data soon.
Another promising BCMA-directed bispecific antibody is teclistamab, which also targets BCMA and CD3. At the 2020 ASCO Annual Meeting, researchers presented preliminary data from a phase I dose-escalation study of the drug in patients with relapsed/refractory MM. The ORR was 78% at the highest weekly treatment dose with a manageable safety profile.9
Alfred L. Garfall, MD, assistant professor of medicine at the University of Pennsylvania’s Perelman School of Medicine and an investigator on the teclistamab study, said the step-up dosing used in the study allowed for greater control of potential toxicities. "It offers a little more control over that initial T-cell activation, compared with CAR T cells, where the full dose is infused and you get what you get," he said.
He also pointed to teclistamab's subcutaneous dosing as a potential benefit for patients down the line.
While there are several different bispecific antibodies targeting BCMA in early phase trials, Dr. Garfall said they are similarly promising at this point.
One of the most exciting advances in the development of bispecific antibodies is the emergence of drugs with targets other than BCMA, Dr. Costa said.
"The BCMA space is becoming very busy with multiple CAR T-cell products, an approved antibody drug conjugate, and now several bispecifics," he said. "So, it's extremely reassuring and refreshing to see validation of new immunotherapy targets."
One of those targets is GPRC5D, which is the target of the bispecific antibody talquetamab.10 The other is cevostamab, which targets FcRH5.11 "These are two brand new targets for MM, and they all showed pretty impressive initial response rates," Dr. Garfall said.
Which Modality Is the Frontrunner?
Will one of these treatment modalities become the new standard of care over the next few years? The experts interviewed for this article said that's unlikely. Instead, there is room for all the different approaches because they each offer some distinct advantages.
"It's too early to make comparisons in terms of efficacy and duration of response, but there are some pretty straightforward comparisons in terms of tradeoffs that are intrinsic to each modality," Dr. Garfall said. "I still think that we're going to end up trying all these different options for patients at one time or another. So, I don't see it as an either/or situation for the other therapies."
CAR T cells appear to have an advantage with their high response rates but, as with bispecific antibodies, they carry significant adverse events like CRS and neurotoxicity. CAR T cells also offer the advantage of being a one-time treatment. However, since administration of this therapy requires apheresis, followed by manufacturing of the CAR T cells, it can take several weeks before patients are treated, which may put the therapies out of reach for patients with rapidly progressing advanced disease.
"CAR T-cell therapy is a one-and-done treatment, which can be very practical for patients because they don't have to have ongoing therapy," Dr. Costa said, "but that comes with a risk of recurrence as those transduced and infused cells tend to fade away over weeks to months."
Bispecific antibodies have the advantage of being "off-the-shelf," so they can be almost immediately deployed for patients. Their step-up dosing may also offer physicians more control in managing side effects, but this is a continuous therapy that must be dosed every two to three weeks and it is too early to know how long the initial responses to therapy will last.
ADCs are available off-the-shelf and their side effects can be managed on an outpatient basis. Their response rates, however, are significantly lower than other modalities.
"[Belantamab] is a drug that could theoretically be given to all patients," Dr. Trudel said. "But the response rates that we are seeing with the ADCs don't match what is seen with the CAR T cells, for example. It's also not a one-shot treatment like CAR T-cell therapies."
The future of immunotherapy treatment in MM is unlikely to be a single-agent treatment, she added. A combination of these therapies is more likely. Studies evaluating ADCs in combination with existing myeloma therapies are already underway.
Dr. Garfall said he wonders whether bringing a combination of the best-performing immunotherapies into the frontline setting could lead to a cure in some patients. "That's a big question. You could theorize both ways about it, but ultimately you just have to test it," he said.
Another big question is how to sequence these therapies, Dr. Mailankody said. For instance, could a patient whose disease relapsed after receiving an BCMA-directed CAR T-cell treatment then receive a BCMA-directed bispecific antibody treatment?
Several research groups, including Dr. Mailankody's, will be evaluating that question in the coming months and years to define what the BCMA expression looks like after treatment. "Sequencing has always been a critical question and challenge for us in treating patients with MM," he said. —By Mary Ellen Schneider
References
- FDA. FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma. Accessed February 8, 2021, from https://www.fda.gov/drugs/drug-approvals-and-databases/fda-granted-accelerated-approval-belantamab-mafodotin-blmf-multiple-myeloma.
- Lonial S, Lee HC, Badros A, et al. Pivotal DREAMM-2 study: single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) refractory to proteasome inhibitors (PIs), immunomodulatory agents, and refractory and/or intolerant to anti-CD38 monoclonal antibodies (mAbs). J Clin Oncol. 2020;38(suppl 15):8536.
- GSK. FDA approves GSK's BLENREP (belantamab mafodotin-blmf) for the treatment of patients with relapsed or refractory multiple myeloma. Accessed February 8, 2021, from https://www.gsk.com/en-gb/media/press-releases/fda-approves-gsk-s-blenrep-belantamab-mafodotin-blmf-for-the-treatment-of-patients-with-relapsed-or-refractory-multiple-myeloma/.
- Kumar SK, Migkou M, Bhutani M, et al. First-in-Human Study of MEDI2228, a BCMA-Targeted ADC in Patients with Relapsed/Refractory Multiple Myeloma. Abstract #179. Presented at the Presented at the 2020 American Society of Hematology Annual Meeting, December 5, 2020.
- Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): Initial KarMMa results. J Clin Oncol. 2020;38(suppl 15):8503.
- Madduri D, Berdeja JG, Usmani SZ, et al. CARTITUDE-1: phase 1b/2 study of ciltacabtagene autoleucel, a B-cell maturation antigen–directed chimeric antigen receptor T cell therapy, in relapsed/refractory multiple myeloma. Abstract #177. Presented at the 2020 American Society of Hematology Annual Meeting, December 5, 2020.
- Mailankody S, Jakubowiak AJ, Htut M, et al. Orvacabtagene autoleucel (orva-cel), a B-cell maturation antigen (BCMA)-directed CAR T cell therapy for patients (pts) with relapsed/refractory multiple myeloma (RRMM): update of the phase 1/2 EVOLVE study (NCT03430011). J Clin Oncol. 2020; 38(suppl 15):8504.
- Costa LJ, Wong SW, Bermudez A, et al. First Clinical Study of the B-Cell Maturation Antigen (BCMA) 2+1 T Cell Engager (TCE) CC-93269 in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Interim Results of a Phase 1 Multicenter Trial. Blood. 2019;134(suppl 1):143.
- Usmani SZ, Mateos MV, Nahi H, et al. Phase I study of teclistamab, a humanized B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in relapsed/refractory multiple myeloma (R/R MM). J Clin Oncol. 2020;38(suppl):100.
- Chari A, Berdeja JG, Oriol A, et al. A Phase 1, First-in-Human Study of Talquetamab, a G Protein-Couple Receptor Family C Group 5 Member D (GPRC5D) x CD3 Bispecific Antibody, in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM). Abstract #290. 2020 American Society of Hematology Annual Meeting, December 5, 2020.
- Cohen AD, Harrison SJ, Krishnan A, et al. Initial Clinical Activity and Safety of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Relapsed/Refractory Multiple Myeloma. Abstract #292. Presented at the 2020 American Society of Hematology Annual Meeting, December 5, 2020.
